Pulmonary thromboembolism as an atypical manifestation of mixed connective tissue disease in a young man: A case report

Abstract

Mixed connective tissue disease is an autoimmune disorder characterized by the presence of various abnormal autoantibodies and systemic involvement. Similar to systemic lupus erythematosus, pulmonary manifestations commonly include interstitial fibrosis, pulmonary hypertension, and pleurisy; however, pulmonary thromboembolism has rarely been reported in mixed connective tissue disease. We report a case of mixed connective tissue disease in which pulmonary thromboembolism was the initial manifestation, as diagnosed by computed tomography angiography. Following glucocorticoid and anticoagulant therapy, the thrombus resolved completely. This case highlights that in patients with mixed connective tissue disease, particularly those presenting with dyspnea or sudden-onset dyspnea, the possibility of pulmonary thromboembolism should not be overlooked.

Introduction

Mixed connective tissue disease (MCTD), first described by Sharp et al. in 1972, ¹ is a distinct autoimmune disorder characterized by overlapping clinical features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis or dermatomyositis (PM/DM), and rheumatoid arthritis (RA). Key diagnostic markers include high-titer speckled-pattern antinuclear antibodies (ANA) and anti-U1 ribonucleoprotein (RNP) antibodies. The disease predominantly affects women (approximately 80% of cases) and commonly involves multiorgan damage to the cardiovascular, pulmonary, renal, musculoskeletal, and gastrointestinal systems. Historically, the status of MCTD as an independent entity was debated because many patients evolved toward defined connective tissue diseases, such as SSc, SLE, RA, PM, or DM. This controversy persisted until 2014, when MCTD was established as a distinct clinical entity. ² No universally accepted diagnostic criteria exist for MCTD, and the American College of Rheumatology (ACR) has not issued formal guidelines. Commonly applied clinical criteria include the Sharp criteria (United States), Alarcón–Segovia criteria (Mexico), Kahn criteria (France), and Kasukawa criteria (Japan). Among these, the Kasukawa criteria demonstrate the highest sensitivity. ³ Nailfold capillaroscopy has also been identified as a valuable diagnostic adjunct. ⁴

Pulmonary involvement in MCTD typically manifests as interstitial fibrosis, pulmonary arterial hypertension, and pleuritis. However, pulmonary thromboembolism has rarely been reported in MCTD. We report a case of MCTD in which pulmonary thromboembolism was the initial manifestation, emphasizing that in patients with MCTD who present with dyspnea, the possibility of pulmonary thromboembolism should be carefully considered.

Case report

Clinical manifestations

A man in his late 30s was admitted to the Affiliated Hospital of Yanbian University, Yanji, China, in early 2022 with a 1-month history of chest tightness and fever (up to 38.8°C) worsening over 10 days. These symptoms were accompanied by chest pain (bilateral lower anterior chest, aggravated by breathing) and exertional dyspnea. The patient initially sought medical attention in the emergency department. Physical examination findings were as follows: (a) body temperature, 38.5°C; (b) facial erythema; (c) coarse breath sounds in both lungs, with fine moist rales; and (d) pulmonary component of the second heart sound louder than the aortic component (P2 > A2), a systolic murmur audible at the tricuspid valve area, and no jugular venous distention. Significant medical history included the following: (a) facial erythematous plaques with scaling (eyebrows, cheeks, temples, and jawline) for 2 years; (b) Raynaud’s phenomenon for 2 years; (c) cervical lymph node tuberculosis was treated 8 years ago; and (d) no relevant family history or other risk factors—such as surgery, malignancy, or prolonged bed rest—for pulmonary embolism (PE) identified.

Laboratory examination and imaging

Laboratory tests showed normal levels of white blood cells, lymphocytes, and procalcitonin (PCT). The erythrocyte sedimentation rate (ESR; 75 mm/h) and high-sensitivity C-reactive protein (>200 mg/L) were markedly elevated. The results revealed elevated fibrinogen (7.55 g/L) and D-dimer (7.46 mg/L) levels, suggesting possible hypercoagulability, as well as prolonged activated partial thromboplastin time (APTT) (45.4 s) with a positive lupus anticoagulant test (LA1/LA2 ratio, 1.21), indicating antiphospholipid syndrome (APS). Autoimmune markers were strongly positive, including high-titer ANA (1:3200, speckled pattern), anti-U1 RNP (>400 RU/mL), and proteinase 3 antineutrophil cytoplasmic antibodies (PR3-ANCA) (185 RU/mL), which, together with elevated immunoglobulin G (IgG) (17.80 g/L) and complement C3 (1.83 g/L), suggested an active autoimmune process such as MCTD or vasculitis. Rheumatoid factor, anti-cyclic citrullinated peptide (CCP) antibodies, and most antiphospholipid antibodies (aPL), except for the lupus anticoagulant, were negative. T-SPOT and purified protein derivative (PPD) tests were both negative. In addition, sputum smear tests and cultures yielded negative results. Echocardiography revealed a small amount of pericardial effusion, and pulmonary artery pressure was generally normal, as assessed by right ventricular pressure. The electrocardiogram (ECG) findings were essentially normal, with no significant abnormalities (Figure 1). Computed tomography (CT) pulmonary angiography (CTPA) revealed patchy filling defects in the pulmonary arteries of both lungs, with slight thickening of local vessels in the proximal pulmonary arteries. No filling defect was observed in the main pulmonary artery trunk. Patchy filling defects were present in the bilateral lower pulmonary arteries, and localized dilation was noted in the proximal segment of the pulmonary artery. The pulmonary veins showed no significant abnormalities (Figure 2).

Figure 1.

ECG is essentially normal without significant changes. ECG: electrocardiogram.

Figure 2.

CTPA revealed patchy filling defects in the pulmonary arteries of both lungs, with slight thickening of local vessels in the proximal pulmonary arteries. CTPA: computed tomography pulmonary angiography.

Diagnosis, treatment, and prognosis

Based on a comprehensive evaluation of medical history, clinical manifestations, and auxiliary examinations and following the Kasukawa criteria (Japan), the patient met the criteria for Raynaud’s phenomenon, anti-U1 RNP antibody positivity, polyarthritis, facial erythema, and elevated serum levels of muscle enzymes; therefore, a diagnosis of MCTD was established. CT angiography (CTA) confirmed the diagnosis of pulmonary thromboembolism. For the management of MCTD with pulmonary thromboembolism, the patient received a combined therapeutic regimen: low–molecular-weight heparin (LMWH; 5000 IU subcutaneously twice daily (SC BID)) for thrombosis, methylprednisolone (60 mg intravenously once daily (IV QD)) to control acute autoimmune activity, and hydroxychloroquine (0.2 g orally twice daily (PO BID) as a baseline immunomodulator. After 7 days, LMWH was replaced with warfarin (5 mg orally once daily (PO QD)) for long-term anticoagulation, with international normalized ratio (INR) monitoring (target range, 2.0–3.0). Three months later, pulmonary artery CTA revealed no thrombus (Figure 3). The reporting of this study conforms to the Case Report (CARE) guidelines. ⁵

Figure 3.

CTPA performed 3 months later showed no thrombus. CTPA: computed tomography pulmonary angiography.

Discussion

The prevalence of MCTD in China remains undefined, and definitive epidemiological data are currently lacking. However, MCTD is not uncommon in clinical practice. Compared with other immune-mediated disorders, MCTD generally carries a more favorable prognosis, although the development of complications involving the lungs, kidneys, or heart may lead to poorer outcomes. Previous literature reports indicate that approximately 75% of patients with MCTD exhibit pulmonary involvement, with the majority being asymptomatic in the early stages. ⁶ Interstitial lung disease (ILD), which initially presents with dry cough, exertional dyspnea, and chest pain, occurs in 30%–50% of patients. These early manifestations closely resemble those of pulmonary thromboembolism.

This case involves a young man who suddenly experienced chest tightness, chest pain, and dyspnea without obvious precipitating factors, accompanied by fever. Prompt investigation was required to determine the cause of these symptoms. Given the patient’s history of cervical lymph node tuberculosis, T-SPOT, PPD, sputum smear, and culture tests were performed upon admission to rule out PE secondary to reactivated or newly acquired pulmonary tuberculosis; all tests returned negative. Notably, Yue Jia et al. ⁷ reported 43 cases of PE caused by pulmonary tuberculosis.

Furthermore, the patient’s history of facial rash and Raynaud’s phenomenon suggested a high likelihood of an immune-mediated disorder. Seronegative APS was also considered. The concept of seronegative APS was first proposed in 2000 to describe patients with classic APS clinical manifestations but negative aPL. ⁸ Among proponents of seronegative APS, two main explanations have been proposed for negative aPL results: (a) consumption of antibodies during acute thrombotic events or (b) gradual depletion of antibodies over time. Although evidence for the former remains limited, studies have reported decreasing aPL titers over time. ⁹ Before diagnosing seronegative APS, it is essential to exclude patients with previously positive aPL that subsequently became negative. In this young man presenting with thromboembolism, there was no history of aPL positivity. All APS tests performed upon admission were negative, and reexamination after 12 weeks also showed negative results. Although the lupus anticoagulant test was weakly positive, the sample was collected after anticoagulant administration, raising the possibility of a false-positive result. Therefore, a diagnosis of seronegative APS was considered unlikely.

Additionally, the patient’s PR3-ANCA level was 185 RU/mL, necessitating differentiation from vasculitis. ANCA-associated vasculitis (AAV) typically affects small- to medium-sized vessels, with pathology characterized by vascular wall inflammation and fibrinoid necrosis. Pulmonary involvement in AAV often presents with cough, hemoptysis, chest tightness, dyspnea, lung shadows or masses, interstitial changes, or pleural effusion. ¹⁰ Figueiredo et al. ¹¹ reported a case of a 17-year-old man with PR3-ANCA positivity who developed acute PE. However, this case exhibited cavitary lesions on chest CT, and bronchial biopsy revealed necrotizing inflammation, leading to a final diagnosis of granulomatosis with polyangiitis (GPA). Although PR3-ANCA was positive in this patient, he lacked typical GPA clinical features, such as nasal or oral inflammation, and characteristic imaging findings, thus not supporting a diagnosis of GPA. Furthermore, CTPA confirmed that the emboli were located in the bilateral lower pulmonary arteries, which is inconsistent with AAV, as it characteristically spares large vessels. ¹²

The treatment of MCTD primarily involves glucocorticoids and disease-modifying antirheumatic drugs (DMARDs). Symptomatic management by relevant specialists is also necessary when multiple organ systems are affected. Glucocorticoids are currently the first-line therapy in clinical practice, as they can rapidly alleviate symptoms during the acute phase. In this case, the patient experienced rapid clinical improvement with glucocorticoid therapy. A recent French study involving 315 patients demonstrated that hydroxychloroquine (HCQ) and glucocorticoids were the cornerstones of MCTD treatment and were sufficient to control disease manifestations in nearly half of the patients, reflecting the generally favorable prognosis of this disease. ¹³

The management of Raynaud’s phenomenon includes avoiding caffeine and smoking as well as maintaining local warmth. ¹⁴ For pharmacological intervention, oral calcium channel blockers (CCBs), such as nifedipine, may be used. Intravenous prostaglandins and topical nitroglycerin have also been shown to be effective. ¹⁵ In this patient, maintaining proper hand warmth led to significant improvement in Raynaud’s phenomenon, eliminating the need for pharmacological treatment.

Anticoagulant therapy is essential for patients with thrombotic risk, although the efficacy of warfarin remains uncertain. The patient was diagnosed in early 2022, and aPL testing was positive upon admission; therefore, the possibility of APS could not be ruled out at that time. According to the 2019 European Society of Cardiology (ESC) guidelines on the diagnosis and management of acute PE, ¹⁶ warfarin was selected for anticoagulation rather than direct oral anticoagulants (DOACs). Heparin was administered during the acute phase before switching to oral warfarin. Pulmonary CTA at 3 months showed no thrombosis, indicating a favorable prognosis. During follow-up, the patient occasionally experienced Raynaud’s phenomenon, but no respiratory symptoms were observed.

Conclusion

In clinical practice, the diagnosis and management of MCTD complicated by acute PE (APE) remain challenging due to limited experience. Once complicated by APE, the condition can progress rapidly. Involvement of large pulmonary vessels or presentation as massive pulmonary thromboembolism significantly increases the risk of mortality. Therefore, in patients with MCTD, particularly those presenting with dyspnea—especially sudden-onset dyspnea—the possibility of pulmonary thromboembolism should not be overlooked, even when considering MCTD-related ILD. Comprehensive chest examination and high-resolution CT (HRCT) are essential. When pulmonary thromboembolism is highly suspected, CTPA should be performed promptly to enable early diagnosis and to maximize the therapeutic window.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605251397846 - Supplemental material for Pulmonary thromboembolism as an atypical manifestation of mixed connective tissue disease in a young man: A case report

Supplemental material, sj-pdf-1-imr-10.1177_03000605251397846 for Pulmonary thromboembolism as an atypical manifestation of mixed connective tissue disease in a young man: A case report by Chunchao Wang, Xinying Cui and Jingchun Jin in Journal of International Medical Research